Hemodialysis access systems for access to a patient's vascular system for exchange of blood between the vascular system and an external processing apparatus are well known in the art. The simplest such system is a catheter alone placed directly in the patient's right jugular vein with the distal end extending into the central venous system, typically into the superior vena cava. Other more complicated systems, for example ports, usually involve indwelling catheters as well. The exchange of blood for hemodialysis treatment typically involves high blood flow rates under conditions designed not to induce shear stress beyond a certain level so as to not cause red cell damage or the activation of platelets.
As with any implanted device, placement of an object that must remain in the patient over a protracted period of time gives rise to the likelihood of blood stream infection promoted by the indwelling device. Infection risk is seriously aggravated by the fact that such devices are frequently handled and manipulated by medical workers, leading to microbial colonization of the catheter's internal surfaces, that is, formation of a biofilm in the lumen. Infection from a biofilm reservoir is much more serious than a simple infection, since it is often impossible to eradicate with conventional means. In refractory cases the device must be explanted to treat the patient effectively. As a result, the literature, both scientific and patent, is replete with hopeful but not definitive suggestions as to how to defeat, or at least hold at bay, catheter related infections.
In describing approaches to preventing or treating catheter infections, authors and practitioners generally refer to “locking” the catheter, but also sometimes use the term “flushing” the catheter. Usage in the case of the term “flushing” is ambiguous, and therefore some explanation of terminology is necessary. With respect to implanted catheters, authors and practitioners typically speak of “locking” a catheter between uses. In this context, “locking” means filling the catheter lumen with a substance that is biocidal or an anticoagulant but preferably both, followed by leaving it there until the catheter has to be used again. (Typically, “locking” a catheter with a given solution also includes in the assumed procedure the follow up event of withdrawing the solution from the catheter before using. for example, a syringe to suck the solution out of the catheter whenever the catheter must he used again.) For example, in the past authors or practitioners have spoken of heparin as a catheter lock. That word usage is relatively unambiguous.
Authors and practitioners have, however, not used the terms “flush” and “flushing” unambiguously. Much of the time “flushing” has a meaning that is familiar to non-experts, namely sending a fluid through the catheter or into it and quickly back out again as a kind of washing. However, a substantial fraction of authors and practitioners also use the terms “flush” and “flushing” as synonymous with “lock” and “locking” as defined above, that is, meaning putting a solution in a catheter and leaving it there for an extended period and then taking it out when the practitioner wants to use infuse the patient or remove fluid from the patient. In this application the former meaning of “flush” and “flushing” is generally intended. However, in reviewing the literature the other usage must be borne in mind.
Antibiotics have been used to treat devices such as catheters to prevent infection, but chronic use of antibiotics as a prophylactic accelerates emergence of antibiotic-resistant bacterial strains. Advances in catheter locks described in the scientific literature and other patent documents have involved the use of a substance generally referred to as taurolidine and/or taurinamide and taurinamide derivatives for routine antimicrobial use, in particular in catheters. Taurolidine and related compounds are biocidal but are known not to induce development of resistant bacterial strains. For example, Sodemann, U.S. Pat. No. 6,166,007, issued Dec. 26, 2000 and Sodemann, U.S. Pat. No. 6,423,706, issued Jul. 23,2002, among others, disclosed use of taurolidinc and other taurinamide-related compounds as part of a catheter lock solution.
Coagulation of the blood inside catheters in or connected to the vascular system has also proven troublesome and many methods have been tried for its prevention, particularly for inhibiting the clogging of the catheter, which can diminish or destroy the catheter's usefulness. It is standard procedure to flush blood from the catheters and then lock them with a heavy-duty anticoagulant, heparin locking solution being the standard. Unfortunately heparin alone lacks biocidal capability, but this deficiency is often ignored.
Current indwelling blood catheter maintenance practices, particularly with respect to hemodialysis catheters, have evolved to the point where current de facto practices require that an extremely high concentration heparin be instilled as a lock between uses. Normally the heparin lock concentration is 5,000 units per ml. By comparison, therapeutic levels in the blood to prevent clotting in patients with disorders whereby their blood to form clots are generally in the range of 0.2 to 0.4 units per ml. It is also known that blood used in laboratory experiments can be maintained in a fluid state (i.e., not clotted) by using a heparin concentration in the range of 5 units or so.
Unfortunately, and contrary to good catheter locking practice, sometimes medical personnel flush heparin—in the flow-through sense—from the catheter directly into the patient instead of drawing it out, e.g., with a syringe. Such events may be accidental or even in some cases deliberate when the practitioner is attempting to unblock a clotted catheter. An important consideration in the use of heparin is that if too much heparin is pushed into the patient's vascular system the patient may become systemically anticoagulated, creating a significant risk to the patient bleeding out, that is, dying of uncontrollable hemorrhage. Further, sonic patients are allergic to heparin. For both reasons, minimizing systemic administration of heparin is important.
U.S. Patents Nos. 6,166,007 and 6,423,706, cited above, disclosed solutions based on taurinamide derivatives, preferably taurolidine, combined with biologically benign salts and corresponding acids, most preferably citrate salts along with citric acid, as catheter locking solutions and solutions for maintaining implants having both antimicrobial and anticoagulant properties. Selection of optimum concentrations of these substances while also controlling the pH of the solution to be generally slightly acidic increases the antimicrobial efficacy of taurolidine in solution.
Other substances could he used as anticoagulants, for example EDTA, enoxaparin sodium, coumarin, indanedione derivative, anisindione, warfarin, protamine sulfate, streptokinase, urokinase, and others. However, the properties of citrate and citric acid in a proper pH balance give special effectiveness to catheter locks of the referenced formulation.
It has been empirically found in practicing the above-referenced patents, however, that sometimes taurolidine reacts with a patient's red blood cells inside the catheter and changes the characteristics of the blood clot that normally forms at the distal end of the catheter. This change sometimes results in clot fragments or nuclei remaining attached to the interior luminal surface of the catheter after the lock solution is withdrawn in preparation for catheter use. The end result of even a small clot fragment attached to the inside of a catheter is at least partial obstruction of flow through the catheter. In the case of hemodialysis catheters, this causes a significant increase in resistance to blood flow in the catheter. Too high a resistance increase may cause blood damage and can also reach an upper limit that requires a reduction in blood flow rate. Such flow resistance interferes with dialysis efficiency and extends dialysis time of treatment.
The formulation of taurolidine with citrate and citric acid described in U.S. Pat. Nos. 6,166,007 and 6,423,706, cited above, has worked well in minimizing catheter-caused infections in hemodialysis patients. Dr. Sodemann, conducted initial trials of these compositions including evaluation of pH values for maximizing the antimicrobial properties of the composition.
Dr. Sodemann and others also performed clinical trials of the final compositions in Europe to obtain approval for commercialization there. The data from Europe demonstrated nearly complete elimination of catheter related bloodstream infection, compared to the rate observed with heparin locks and simultaneous achievement of a catheter patency rate (the inverse of the rate of complications due to blood flow resistance during hemodialysis) comparable to that of heparin lock solutions.
Subsequently, in 2001 and 2002, however, the University of Alabama Medical Center conducted a hemodialysis clinical trial using the Sodemann taurolidine lock formulation. The clinical results confirmed the low infection rate with the taurolidine based lock solution. However, this trial experienced a high rate of catheter patency complications compared with the heparin lock control group. Allon, M., “Prophylaxis against dialysis catheter-related bacteremia with a novel antimicrobial lock solution,” Clinical Infec. Dis. 2003(June) 15; 36 (12): 1539-44.
The usual intervention to correct observed high flow resistance in a hemodialysis catheter is a clot-lysing procedure, which cleans out the catheter. Whenever the University of Alabama practitioners experienced a patency complication, they would perform the clot lysing procedure, which was rapid and 100% successful. This result suggested that the flow resistance was caused by internal adhesion to the catheter. The calculation of catheter patency complication intervention in the University of Alabama study was determined by taking the number of lysing procedures performed during the study period and dividing it by the sum of patient days in the trial. The patency complication rate for the group receiving the taurolidine-based locking solution was approximately 4 times higher than for the heparin lock group.
In hemodialysis. blood is withdrawn from the patient via a catheter lumen with its tip in a major blood supply. The blood enters a machine which removes toxins and water from the blood. In U. S. hemodialysis practice. unlike European practice, the blood flow rate is higher and typically approximately 400 ml/min. In order not to damage blood cells at this flow rate, practitioners monitor the flow resistance in the catheter and if the resistance increases above an alarm setting the operator must clear the catheter or slow down the flow. (Lower flow rate is necessary in such situations because the combination of high flow rates and obstructions creates eddies and other non-laminar flow conditions that create shear forces that damage blood cells.) However, slower flow rates require a considerable increase in the time of dialysis to achieve the same level of toxin removal, lengthening the time necessary for an effective hemodialysis session. Longer sessions lower both patient acceptance and clinic productivity.
Several differences in medical practice between the European trials and the U. S. trials probably contributed to the difference in result. Especially significant was that higher blood flow rates are set during dialysis in the U. S. and a different catheter was used in the U. S. clinical trials.
In addition, careful observation taught that, after instillation of a lock solution into a catheter, a small amount of lock solution flows out of the catheter into the patient's vascular system. The lost catheter lock is replaced by blood in the distal tip region of the catheter. This phenomenon is described by Polaschegg, published U.S. Patent Application No. 2004/0156908 A1, paragraphs [0022], [0026]. Polaschegg further describes at paragraphs [0026] to [0027] a related observation, systemic anticoagulation in patients due to transfer of heparin locking solution. This observation has also been reported in medical journals, e.g., as cited in Polaschegg paragraph [0026].
Blood that enters the distal tip portion of the catheter by virtue of being interchanged with locking solution quickly becomes stagnant and therefore typically forms a clot inside the catheter near the distal tip, notwithstanding the presence of high-concentration heparin in the catheter. In hemodialysis catheters and other catheters in the vascular system, the clot that forms in the distal tip portion is withdrawn during conventional preparatory steps prior to initiating, for example, a hemodialysis session. These preparatory steps are the withdrawal of the lock solution, followed by a back flush with a small amount of saline to clear any residual blood or lock in the catheter. The withdrawn material (the lock solution, the clot and some blood) is sucked into a syringe and is discarded.
However, efforts to withdraw the intra-luminal clot are not always effective. Even in current practice, patency complications still occur at a relatively high rate even with high concentration heparin. Any blood clot or clot fragment adhering to the luminal surface of a catheter increases blood flow resistance during treatment, especially at the high blood flows typical of American hemodialysis. Established practices in hemodialysis clinics set a maximum allowable flow resistance in the blood flow path, inferred from increased pressures and decreased flow rates, that must not be exceeded as this may cause damage to red cells and may activate platelets, triggering a clotting response. Consequently, alarms are incorporated in hemodialysis machines to warn the nurse when, e.g., pressure levels are exceeded. Corrective action options are limited and mainly consist of slowing the blood flow rate or stopping the session and performing a catheter clot lysing procedure to open up the catheters to restore patency. In either case, the interventions are a major inconvenience to the patient and diminish the operational efficiency of the hemodialysis clinic.
The trial results by Dr Allon were examined by researchers in a group of experiments at the Naval Blood Laboratory and Boston University Medical School. These experiments determined that blood in contact with high concentration taurolidine solution (such as occurs at the interface between blood and taurolidine locking solution in a catheter) underwent changes, including morphological changes to red cells that did not happen with exposure to just heparin. However, the researchers were not able to determine exactly how their results were relevant to the findings in the University of Alabama clinical trial.
Additional experiments were undertaken seeking to determine scientifically the reasons for the different results. This work comprised in vitro experiments with modifications to the taurolidine-based lock formulation. Testing was done with fresh human blood using silicone rubber catheters commonly used in U. S. hemodialysis practice. Catheter lock and later blood test articles were subjected to conditions simulating as much as possible the environment that occurs in in vivo hemodialysis. Several catheters were tested simultaneously.
Test catheters were mounted in a vertical orientation and filled with various lock solution formulations. The distal tip was placed in a beaker containing fresh blood and blood was pulled into the catheter for a distance of about 3 centimeters. The distal tip and the proximal tip of each catheter were clamped shut. The distal portion of the catheter was immersed in saline at ˜99° F. for 3 days. This time period was comparable to the longest quiescent time period between live hemodialysis sessions. Test specimens included a conventional heparin lock, taurolidine based locks at various pH conditions, and taurolidine locks with and without PVP additives.
The catheter contents were observed visually during the three day time periods. The catheters themselves were translucent and the material holding the saline and the catheter allowed easy visual observation.
The first test sequence used the taurolidine lock in commercial use in Europe and a conventional heparin lock at 5,000 units per ml. It was observed that the high concentration heparin lock behaved very differently with respect to clotting compared to the taurolidine formulation. With respect to the heparin lock, clotting of the blood in the catheter started on the end of the blood segment away from the blood-catheter lock interface. With the taurolidine based catheter lock. the blood started clotting right at the blood-catheter lock interface. In addition, the distal end clot was different in color. The clot formed with the heparin lock was reddish brown, but the clot formed with the taurolidine-based lock solution was black, suggesting the formation of met-hemoglobin. The presence of met-hemoglobin suggests damage to red blood cells by some agent.
Tests were also performed to simulate the procedure that occurs in preparation for hemodialysis session. In a hemodialysis clinic, a nurse withdraws the lock solution from the catheter with a syringe and the catheter is flushed with 10 ml of saline prior to the hook up to the hemodialysis machine. In the in vitro study referred to above. at the end of the 3 day quiescent period, a syringe was attached to the proximal end of the catheter and the clamp on the distal end was removed. The distal tip was then immersed in saline. A syringe was used to withdraw the catheter contents.
It was noted that the clot in the heparin based locking solution could be easily removed intact from the catheter while the clot in the taurolidine based experiments fragmented easily and crumbled. (One test in which the pH of the taurolidine-based locking solution was raised to 6 resulted in less met-hemoglobin in the distal end clot but did not completely solve the problem.) The solidity and mechanical strength of the clots were qualitatively compared by compressing them with a small rod. It was observed that the heparin clot was resilient and similar to the behavior of soft rubber while the clot formed in the taurolidine-based locking solution did not have any resiliency and broke apart easily.
Also, in the catheters containing the taurolidine-based locking solution the procedure often did not completely remove the clot at the distal end. When the clot broke up, fragments remained adhered to the lumen surface of the catheter. Subsequently, in a like manner to the actual clinical situation, the catheter was flushed vigorously with a 10 ml saline solution to determine if the clot fragment attachment could be broken away. This flushing action did not usually dislodge the adhered fragments. In summary, the clot in the catheters containing the heparin locking solution disengaged easily and completely, while the clot in the catheters containing the taurolidine-based locking solution fragmented, with portions remaining stuck to the catheter lumen even after the flush procedure.
These tests comparing the heparin locking solution with a taurolidine-based locking solution suggested that the potency problems experienced in the U. S. clinical trial at the University of Alabama were explained by difference in the nature of the clot formed at the distal end of the catheter with different locking solutions. During the Naval Blood Laboratory/Boston University Medical School experiments referred to above, it was determined that, with one exception, modifications of the taurolidine formulation did not affect the character of the distal tip clot. It was determined that the addition of very low concentrations of heparin (final concentration about 100 units per ml) to the taurolidine formulation minimized or eliminated the evidently taurolidine-induced changes to the character of the clots.
Based on this result, in vitro experiments were also undertaken with a low concentration of heparin added to a test specimen of the standard taurolidine formulation. This solution formulation was also subjected to simulated conditions during the simulated quiescent period. The resulting observation was that the distal tip clot was able to be completely removed intact just as if high concentrations of heparin had been used and its mechanical properties and appearance were similar to the high heparin concentration samples.
However, heparin is a dangerous substance demanding respect. It is usually given systemically to patients who are suffering dangerous disorders involving clotting, such as acute thrombo-embolism. unstable angina, and active thombosis, which are life threatening or cause severe harm. Common complications of heparin administration are internal bleeding and heparin allergy, which can manifest in severe systemic clotting. In any patient, too high a level of heparin will cause hemorrhaging. For hemodialysis patients, however, bleeding is a special problem, since many such patients have a reduced tendency to clot. It is an object of the current invention to provide a level of heparin addition to taurolidine-based catheter lock solutions that will eliminate or minimize the claimer that heparin infused into a patient will prompt uncontrolled bleeding.